The discovery of TRAIL and its receptors is providing insights into mechanisms of tumor suppression in vivo as well as hope for the development of novel cancer therapies. TRAIL (Tumor Necrosis Factor Related Apoptosis Inducing Ligand) is a potent inducer of cancer but not most normal cell death. Ongoing work in this laboratory has identified one of the TRAIL receptors, KILLER/DR5, as a p53 target gene which can also be regulated by p53-independent pathways including dexamethasone, Interferon gamma and bile acids. We and others have identified possible mechanisms of cancer cell resistance to killing by TRAIL including loss of pro-apoptotic TRAIL receptor expression (DR4) in nasopharyngeal and other cancers, increase of anti apoptotic TRAIL decoy receptor expression in gastrointestinal cancers (TRID), and increased cFLIP expression or loss of caspase 8 expression through hypermethylation in neuroblastoma. The utility of TRAIL has not been explored in Esophageal Squamous Cell Cancer (ESCC). We have preliminary evidence that TRAIL can effectively induce apoptotic death in ESCC and that in some cases Bcl-XL over expression may be uniquely contributing to TRAIL resistance in ESCC. Bcl-XL was also recently recovered by our group as an inhibitor of TRAIL in a genetic screen using colorectal cancer cells and we have found that Bax-/- colon cancer cells are TRAIL resistant. Our current proposal has the following goals to address the hypothesis that TRAIL may be useful in ESCC therapy and that defects in TRAIL signaling may contribute to therapeutic resistance in ESCC: Specific Aim #1: To delineate the mechanisms of TRAIL sensitivity and resistance in esophageal cancer. Specific Aim #2: Investigate the role of TRAIL receptors in p53-mediated cell death and chemosensitivity in esophageal cancer and normal esophagus. Specific Aim #3: Investigate the physiological consequences of targeting TRAIL decoy expression to esophageal epithelium. Specific Aim #4: Investigate the consequences of manipulation of the TRAIL pathway in an esophagus reconstruction model. Our studies should provide important insights into the involvement of the TRAIL death pathway and downstream signals in esophageal cancer and susceptibility to TRAIL-induced apoptosis. We will take advantage of integrated approaches with Projects 1 and 2, along with use of the core facilities.